Health disparity in use of novel agents for first-line therapy in Black and White patients with chronic lymphocytic leukemia in the Department of Veterans Affairs

BACKGROUND: Novel agents (NAs) (ibrutinib, idelalisib, and venetoclax) were first introduced in 2013 as therapeutic options to treat chronic lymphocytic leukemia (CLL). OBJECTIVES: To determine if the uptake of NAs for first-line treatment was similar in Black and White patients with CLL treated in the Department of Veterans Affairs (VA). METHODS: We conducted a retrospective cohort study including adults with CLL managed in the VA from October 1, 2013, to September 30, 2017. Descriptive statistics were used to summarize demographic data, and appropriate bivariable statistical tests were used to compare NA use, baseline characteristics, health outcomes, and complications. A multivariable logistic regression model was used to identify factors associated with uptake of NAs. The study included 565 patients; 86% were White and 14% were Black. Black patients were younger than White patients (median age [66 vs 69 years; P < 0.01]) but had similar median baseline Charlson comorbidity scores (4 vs 5). RESULTS: Overall, Black patients were less likely to receive NAs than White patients (14% vs 26%; P = 0.02). The gap narrowed over the study period: 4% vs 17% (2014), 13% vs 25% (2015), 17% vs 33% (2016), and 31% vs 33% (2017). Black race (P = 0.02) and fiscal year (P < 0.01) were the only variables significantly associated with NA use in the multivariable model. Health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns. CONCLUSIONS: This is the first study to identify a potential health disparity with respect to use of NAs among Black and White patients with CLL treated in the VA. Fortunately, health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns.


Plain language summary
New agents have been released, and patients who take these newer agents tend to live longer than those taking older agents. In our study, Black patients with chronic lymphocytic leukemia (CLL) were less likely to receive the newest CLL treatments as first-line compared with White patients with CLL, even after using special statistical methods to account for other important differences between the groups. Fortunately, health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns.
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia, with a median age of diagnosis of 70 years. 1 Older White male individuals have the greatest incidence of CLL, but Black male individuals are also at risk, with Black patients diagnosed at a younger age than White patients (mean age at diagnosis of 67 vs 70 years). 1 The US veteran population mirrors these CLL risk factors: 46% of veterans are at least aged 65 years, 82% are White, and 91% are male. 2 The heterogeneous nature of CLL ranges from an indolent course, requiring a watchand-wait method in which treatment is not initiated for many years, to an aggressive disease in which treatment is initiated soon after diagnosis. In the United States, overall age-adjusted 5-year survival estimates have markedly improved to greater than 80%. 1 Although survival rates have improved overall, outcomes in CLL demonstrate inferior survival among Black patients, with a 5-year survival rate of only 64%. 3 Black patients have also presented with factors associated with worse outcomes, including lower median hemoglobin levels, higher β2-microglobulin levels, and more unmutated IGHV gene expression, ZAP70 expression, and chromosome 17p or 11q deletion. 4 Black race has been associated with worse outcomes in other malignancies as well. For instance, the 5-year survival rate for Black patients with hematologic malignancies remains inferior to the general population. 4 With respect to racial disparities in localized melanoma and renal cell carcinoma treatment since the introduction of novel agents (NAs), a 2016 analysis found disproportionate benefit favoring non-Hispanic White patients and thereby broadening the survival gap with minority populations. 5 However, the study did not observe any racial disparities related to the use of NAs but rather that Black patients had worse outcomes regardless of the treatment modality. Given that Black race is associated with several high-risk features, Black patients might need to receive NAs in higher proportions that exceed that of non-Hispanic White patients. The differences in outcomes appear to be principally related to limitations in access to medical care, later stage at diagnosis, economic factors, and disparities in treatment. In a study of men with prostate cancer, 6 most participants were willing to discuss clinical trial participation, but Black men were significantly less willing than White men, thus less likely to enroll and potentially benefit from NAs in clinical trials. The differences in outcomes might also be related to limitations in access to medical care.
In another study of patients with multiple myeloma, type of insurance was significantly associated with receipt of NAs. 7  With regard to CLL, the "NAs" ibrutinib (Bruton tyrosine kinase inhibitor, US Food and Drug Association-approved for CLL in February 2014), 8 idelalisib (PI3 kinase inhibitor, July 2014), 9 and venetoclax (BCL-2 inhibitor, April 2016) 10 function at the gateway of dysregulated enzyme pathways. Randomized clinical trials, including RESONATE (relapsed/refractory ibrutinib) and RESONATE-2 (first-line ibrutinib), 11,12 have demonstrated the ability of ibrutinib to improve survival compared with chemotherapy (CT)-based treatments. A follow-up 6-year analysis of the RESONATE trial reported statistically significant improvement in progression-free survival, overall survival, and overall response rate with ibrutinib. 13 Importantly, these NAs are available as oral therapies, as opposed to traditional chemotherapies, most of which are intravenous only.
NAs are now featured prominently in the CLL clinical practice and treatment guidelines. 14-17 For patients with high-risk disease (patients with del[17p], del[11q], unmutated IGHV, or mutated TP53), regardless of age and comorbidities, the use of NAs is recommended. 18 As the incidence of CLL increases, with an older, more diverse population undergoing treatment, use of NAs is expected to rise.
Despite the increasing number of treatment options for CLL, few studies have focused on racial disparities between Black and White patients regarding emerging CLL treatments, like the NAs. Black and White patients benefit equally from traditional CLL treatments. 19 Among Black patients, the higher prevalence of high-risk features for which NAs are recommended might predict a higher rate of novel treatment receipt compared with White patients. The Veterans Affairs (VA) is the largest equalaccess health care system in the United States, so it is expected that VA patients should have equal access to these NAs. We hypothesized that the uptake of NAs for from October 1, 2013, to September 30, 2017 (index period), were included in this analysis. NAs were ibrutinib, idelalisib, and venetoclax. CT/CIT therapies were bendamustine + rituximab; fludarabine + rituximab: fludarabine + cyclophosphamide + rituximab; pentostatin + cyclophosphamide + rituximab; chlorambucil; CD20 (rituximab or ofatumumab or obinutuzumab); and other (alemtuzumab or lenalidomide). Patients were included if they had a diagnosis code for CLL (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 204.10, 204.11, or 204.12 or ICD-10-CM codes C91.10, C91.11, or C91.12) at a VA facility from October 1, 2013, to September 30, 2017, received at least 1 of 9 therapies for CLL, and were at least aged 18 years at the date of CLL diagnosis. Patients in clinical trials and those who did not have at least 6 months of follow-up were excluded from this analysis. We chose a minimum follow-up period of 6 months based on a prior real-world study by Seung et al. 21 Each patient chart was reviewed manually, by trained data abstractors, to confirm the CLL diagnosis and to collect information that could not be readily obtained by electronic means, including confirmation of line of therapy. Baseline demographics, health outcomes, and complications were determined for these patients. Data from the 20 years prior to the CLL treatment initiation date were used to define the baseline variables. Data in the 6 months after CLL treatment initiation were used to identify health outcomes (time from diagnosis to initiation, time from initiation to discontinuation, time from initiation to end of follow-up, time from discontinuation to next treatment, initiation to death, discontinuation to death, emergency department visits, urgent care visits, hospital admissions, and death) and complications (diffuse large B-cell lymphoma, Hodgkin lymphoma, stem cell transplant, skin cancer, lung cancer, bladder cancer, and prostate cancer); patients who did not have at least 6 months of follow-up were excluded from this analysis.
Patient race was established by collecting the race that was recorded in the patient's EHR, by VA personnel, during all patient encounters up to 20 years prior to the CLL diagnosis date. The study team assigned patient race based on the most common race that was coded when all those encounters were taken into consideration. Only patients with a race of White or Black were included in this analysis because those 2 racial groups made up more than 95% of all patients, so there were too few patients in the other racial groups for meaningful comparisons. Likewise, more than 95% of patients were recorded as non-Hispanic, so there were too few patients for a Hispanic ethnicity-based comparison.

first-line treatment of CLL would be similar in Black and
White patients managed in the VA.

DATA SOURCE
This was a retrospective observational study, which included adult patients with a confirmed diagnosis of CLL managed in the 18 Veterans Integrated Service Networks in the national VA from October 1, 2013, to September 30, 2017 (Supplementary Figure 1, available in online article).
The study period was based on date of first NA approval for CLL, regardless of line of therapy, to the end of the latest full fiscal year (FY) of data available for the VA at the time of analysis. This study was approved by the University of Texas Health San Antonio Institutional Review Board (HSC-18-712H) and the South Texas Veterans Health Care System Research & Development Committee (VA0003). Electronic data were extracted from the VA electronic medical record. Start and stop dates for 9 common CLL therapies were reviewed manually by a pharmacist to determine first-line therapies.
A thorough description of the data source was previously published. 2 The VA has health care facilities in all 50 states and maintains an electronic health record (EHR) system, which includes administrative, clinical, laboratory, and pharmacy data repositories. These repositories include data from both hospital and clinic settings. Furthermore, the VA system maintains a vital status file that enables investigators to determine patient mortality, even when it occurs outside of the clinic or hospital. Additionally, the VA captures disability and socioeconomic status as VA Priority Group; Group 1 has the greatest disability, Groups 2-6 have the lowest income, and Groups 7-8 have the highest income. 20 Four national VA databases, namely the VA Medical SAS Datasets (both inpatient and outpatient), the VA Vital Status File, the VA Decision Support System Datasets, and the VA Assistant Deputy Under Secretary of Health Annual Enrollment Files, were linked together using a unique patient identifier to develop an analytic dataset of patient data. More than 100 variables of interest were designed and created from the electronic data systems, which were populated with existing data generated during patient care and billing.

STUDY POPULATION
Adult patients (aged ≥18 years) with CLL, in the VA, who initiated first-line treatment with 1 of 9 CLL treatments (3 NAs and 6 CT/chemoimmunotherapy [CIT] treatments),

Results
The study included 565 patients; 86% White and 14% Black (Table 1). Patients had a median (interquartile range) age of 69 (64-75) years; 99% were male. Frequent comorbidities at baseline were diabetes, chronic obstructive pulmonary disease, and hypertension. The median (interquartile range) age-adjusted Charlson comorbidity score was 5 (4-6). Ibrutinib accounted for 97% of the NA use in this study. Black patients were younger than White patients (Table 1), but both groups had similar baseline comorbidity scores. Overall, Black patients were less likely to receive NAs than White patients (14% vs 26%; P = 0.02). The proportion of patients receiving a NA increased over time for both groups, and the gap between groups narrowed/closed over the study period ( Figure 1).
Patient age (P < 0.01), male sex (P = 0.09), peptic ulcer disease (P = 0.10), deep vein thrombosis (P = 0.10), intestinal disorders (P = 0.03), Priority Group 7-8 (P = 0.06), and antihypertensives (P = 0.03) were different in Black and White patients at baseline (P < 0.1) and were therefore used as model covariates. Additionally, FY was added as an additional covariate to the model because of the association between NA use and FY. In the multivariable model, with NA use as the dependent variable, Black race as the independent variable, and the aforementioned variables as

STATISTICAL ANALYSIS
Descriptive statistics were used to summarize and compare baseline characteristics, health outcomes, and complications. A nominal logistic regression model was used to determine the impact of Black race (independent variable; Black/White) on receipt of NAs (dependent variable; yes/no). Baseline patient characteristics for the 2 groups (Black vs White) were compared using the chisquare test and Fisher exact test for categorical variables and t-test and Mann-Whitney U-test for continuous variables. Covariates for the multivariable regression model were based on differences in baseline characteristics (P < 0.10) and clinician judgment about additional variables (ie, FY of treatment) that warranted inclusion in the model. Ultimately, Black race, patient age, male sex, peptic ulcer disease, deep vein thrombosis, intestinal disorders, VA Priority Group 7-8 (a marker of socioeconomic status), antihypertensives, and FY were included as covariates in the multivariable model.
All analyses were conducted using JMP Pro 14 and SAS statistical software (SAS Institute, Inc.). The use of data from a structured EHR database reduced, but did not eliminate, missing values. When comparing specific characteristics between groups of interest, variables with unknown/missing data were not included in the analyses.

TABLE 1 Baseline Characteristics (continued)
White patients was greatest for the first study year and progressively narrowed/closed in subsequent years.
Prior to the introduction of NAs in CLL management, CT/CIT was the standard of care. Notably, in our study, more Black patients received CT/CIT and more White patients received NAs as first-line therapy over the study period. This difference in CLL treatment for Black and White patients is consistent with a prior CLL study 4 and is possibly attributable to differences in patient age between the groups. This association between patient age and race led to our inclusion of age as a covariate in our multivariable model.
Higher comorbidities in Black patients has been postulated as a potential reason for racial disparities in cancer care; however, in our study, Black and White patients had a similar age-adjusted Charlson comorbidity score. Other studies have also demonstrated similar mean comorbidity scores between Black and White patients within the VA. 22 In contrast, studies in non-VA populations generally report more high-risk features, worse disease biology, medical comorbidities, and higher Charlson scores in Black patients compared with White patients. 4,22,23 However, the VA population as a whole generally has more comorbid conditions the covariates, the only variables that were independently predictive of NA use were Black race and FY (Table 2).
In unadjusted analyses, Black and White patients experienced similar health outcomes and complications, except for prostate cancer, which was more common in Black patients (16% vs 8%; P < 0.01) ( Table 3).

Discussion
This is the first study to identify a potential health disparity with respect to uptake of NAs among Black and White patients treated for CLL in the VA. Because Black and White patients benefit equally from traditional CLL treatments, 19 equal access to new CLL treatments is critical. Fortunately, in this study, observed health outcomes and complications, except for prostate cancer, were similar for Black and White patients despite the difference in receipt of NAs. This study did not assess quality of life (QOL) for the 2 groups, and study authors were unable to find existing literature regarding QOL for Black and White patients treated with NAs for CLL in the VA. This study did not assess other health outcomes, including response to therapy, progression-free survival, or QOL. The observed disparity between Black and lower among Black patients than White patients. However, there was no statistical difference when compared by patient age and comorbidities, as Black patients possessed comorbidities that were associated with less use of NAs. 25 In our study, even after controlling for several covariates, including patient age and divergent comorbidities, a statistically significant difference remained in the uptake of NAs. Long before the advent of NAs, racial disparities regarding therapeutic agent use have been reported for other hematologic malignancies. A study regarding patients with diffuse large B-cell lymphoma found similar trends in the use of CIT after the introduction of NAs. Over time, an increase in use occurred for patients across all racial categories; however, Black patients were still less likely to receive CIT as the years progressed. 26 Other studies have also reported differences in the uptake of CT by race. In patients with acute myeloid leukemia, lower proportions of Black patients received appropriate treatment with CT compared with White patients. 27 In another study, the likelihood of undergoing hematopoietic stem cell transplant for leukemia, lymphoma, and multiple myeloma was shown to be significantly lower for Black patients compared with White patients. 28 The disparity in the uptake of NAs is likely multifactorial, including barriers at the level of patients, clinicians, and institutions. [29][30][31] It is evident that across and within sociodemographic groups there are major differences in the environment where people live. For example, neighborhoods have often been seen as the result of sorting that occurred secondary to socioeconomic differences. One study highlights the importance of residential segregation in health care disparities. 32 Black Americans that lived in neighborhoods separate from White Americans, as well as in inner cities, had less access to primary care providers. 32 This example of structural discrimination creates social risk factors that adversely affect health outcomes. The complexity of patients seeking cancer care and fragmentation of the health care system can also pose a challenging dilemma. Providers' contribution to racial disparities has not been well established. However, one hypothesis describes the process of medical decision-making that providers go through and the implicit bias (both unconscious and conscious) about individuals that may result in disparate treatments. 33 This theory, still in its infancy, possesses its own obstacles as no provider wants to be subject to underlying racial bias, but it must be recognized and addressed.

LIMITATIONS
The current study provides insights into potential racial disparities in the uptake of NAs between Black and White patients treated for CLL in the VA; however, we exercise than the general US population, which may limit the generalizability of these findings to non-VA populations. 24 Socioeconomic status is frequently discussed as a potential prognostic factor because of its potential to influence several important components in the management of patients with cancer. It has been suggested that patients with cancer belonging to minority racial or ethnic groups, including Black patients, may have poorer access to health care facilities, leading to potential delay in diagnosis and more advanced disease at presentation. In this study, Black and White patients were statistically similar with respect to VA Priority Groups (a marker of socioeconomic status).
Racial disparities regarding NA use has been documented in patients with multiple myeloma. 25    Therefore, one gets a much more complete picture of the patient by looking at the problem list from many encounters. In this study, we looked at the problem lists from all inpatient and outpatient encounters for many years prior to CLL treatment initiation to get a much more complete picture of the patient's comorbidities. This is a strength of the study. Studies of clinical trials and equalaccess systems provide support for the idea that equal treatment will yield similar outcomes between patients of racial and ethnic minority groups and White patients with similar diseases. 35 However, our results indicate that racial disparities exist, even with the elimination of health care accessrelated factors, such as the ability to pay for care, suggesting that racial disparities in the uptake of NAs within the VA is likely multifactorial and could include factors related to patient and/ or physician preference in regards to the use and prescribing of newly approved agents. This could be why the prescribing gap was greater in the early study years but narrowed/closed by the final study year. The uptake of NAs used throughout the study period was similar to other studies within the time period. 21,36 With the rapid change in survival outcomes, fixed treatment durations, and improved toxicity profiles, NAs have completely shifted the treatment landscape of first-line treatment for CLL in the last decade.

Conclusions
This is the first study to identify a potential health disparity with respect to use of NAs among Black and White patients treated with CLL in the VA. Fortunately, health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns. Further studies should explore rapidity of progression, lymph node size, laboratory parameters, and time from diagnosis to treatment) are critical in the choice of targeted therapies.
Patient preference and logistical differences in administration of these therapies (ie, prolonged oral administration by the patient themselves vs controlled, time-limited, intravenous therapy) may have also influenced patient or physician preference to choose one therapy over another. Unfortunately, this was a retrospective study and, therefore, could not capture information on patient or physician thoughts or preferences regarding method of administration and if it influenced treatment selection. 32,33 Furthermore, we did not have access to detailed information on VA facility, state, or physician prescribing behavior. Availability of these additional variables could have improved the multivariable regression model and enabled multilevel modeling and cluster analysis.
We did not collect data on patients who were excluded from the study; therefore, we cannot determine if included and excluded patients were similar. There were no missing data for any of the baseline, health outcomes, and complications variables depicted in Tables 1 and 2, except for 7 patients who were missing the exact date of CLL diagnosis. Those 7 patients were excluded from the "time from diagnosis to treatment initiation" calculation.
Some baseline variables, like patient age, were calculated at the time of CLL treatment initiation, using dates. Other variables, like patient comorbidities, were obtained from an EHR that was built for patient care, not research. A patient's problem list for a given health encounter contains the problems managed during that encounter. Not all chronic conditions are listed for every encounter.